Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53
Inhibition of mutant Kras and p53-driven pancreatic carcinogenesis by atorvastatin: Mainly via targeting of the farnesylated DNAJA1 in chaperoning mutant p53
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DOI：
10.1002/mc.23097
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发表时间：
2019-08-09
影响因子：
4.6
通讯作者：
Yang, Guang-Yu
中科院分区：
文献类型：
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作者：
Xu, Dandan;Tong, Xin;Yang, Guang-Yu
最近的研究表明，使用他汀类药物抑制甲羟戊酸途径会损害突变型 p53 与 DnaJ 亚家族 A 成员 1 (DNAJA1) 的相互作用，从而诱导突变型 p53 降解。然而，DNAJA1 的 C 末端带有用于法呢基化的 CAAX 盒，在客户蛋白（例如突变体 p53）的结合、折叠和易位中的作用尚不清楚。在本研究中，我们使用了胰腺癌基因工程小鼠模型，结果表明阿托伐他汀显着提高了动物的存活率并抑制了胰腺癌的发生。胰腺腺泡、胰腺上皮内瘤变病变和腺癌中突变型 p53 蛋白的积累显着减少。补充法尼基焦磷酸（蛋白质法尼基化的底物）可挽救阿托伐他汀诱导的胰腺癌细胞中突变型 p53 降解。 Tipifarnib 是一种法尼基转移酶抑制剂，反映了阿托伐他汀对突变体 p53 的作用，以剂量依赖性方式降解突变体 p53，并将法尼基化 DNAJA1 转化为非法尼基化 DNAJA1。法尼基转移酶基因敲除也显着促进突变体 p53 降解。通过抗 DNAJA1 或 p53 抗体进行的免疫共沉淀证实了突变型 p53 和 DNAJA1 的直接相互作用，并且较高剂量的阿托伐他汀治疗将更多的法尼基化 DNAJA1 转化为非法尼基化 DNAJA1，而被 DNAJA1 拉低的突变型 p53 则少得多。引人注目的是，C394S 突变体 DNAJA1（其中 CAAX 盒的半胱氨酸突变为丝氨酸）不再能够被法尼基化，并且失去了维持突变体 p53 稳定的能力。我们的结果表明，法尼基化 DNAJA1 是维持突变 p53 稳定的关键伴侣，阿托伐他汀靶向法尼基化 DNAJA1 对于抑制 p53 突变癌症至关重要。
Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.